Regulation of Intestinal Mucosal Injury and Repair after Trauma/Hemorrhagic shock. PI: David J. Hackam, MD, PhD The long-term goal of the current proposal is to define the mechanisms that lead to the development of intestinal mucosal injury after trauma/hemorrhagic shock, and to develop novel therapeutic strategies to restore intestinal mucosal integrity after injury has occurred. Trauma/hemorrhagic shock is a leading cause of morbidity and mortality in children and adults, in part due to the development of systemic sepsis and multi-system organ injury (MSOF) several days after the initial injury has occurred. The mechanisms that lead to MSOF after trauma remain incompletely understood, yet a breakdown of the intestinal barrier with translocation of enteric bacteria has been shown to play a role in its development. We now hypothesize that activation of the innate immune system of the injured host damages the intestinal mucosal barrier, and that strategies that reduce innate immune system activation will maintain barrier integrity after trauma. To test this hypothesis, we propose the following aims: Aim 1. To determine the role of enterocyte innate immune receptors Toll like receptor 4 (TLR4) and Toll like Receptor 9 (TLR9) in the pathogenesis of intestinal mucosal injury after trauma/hemorrhagic shock. Aim 2. To assess the role of TLR9 activation with CpG-DNA in limiting TLR4 signaling in enterocytes via effects on IRAK-M signaling Aim 3. To determine the role of TLR9 activation with CpG-DNA in protecting against intestinal mucosal injury after trauma/hemorrhagic shock. We will seek to address these aims using a variety of cell biological and physiological techniques using cultured cells, primary enterocytes and in several strains of mice, including mice strains that we have engineered with mutations in innate immune receptor signaling or expression. RELEVANCE (See instructions): The public health relevance of the current proposal lies in the fact that we are seeking to minimze the morbidity and mortality after trauma, which is currently the leading cause of death and disablity in children and young adults.